scholarly journals High glucose-induced fibronectin upregulation in cultured mesangial cells involves caveolin-1-dependent RhoA-GTP activation via Src kinase

2016 ◽  
Vol 14 (1) ◽  
pp. 963-968 ◽  
Author(s):  
YONGFU LU ◽  
LIHONG TANG ◽  
YIQIAO LI ◽  
QIANG HE
Keyword(s):  
High Glucose ◽  
Mesangial Cells ◽  
Src Kinase ◽  
Caveolin 1

Akt and RhoA activation in response to high glucose require caveolin-1 phosphorylation in mesangial cells

2014 ◽  
Vol 306 (11) ◽  
pp. F1308-F1317 ◽  
Author(s):  
Su-Zhen Wu ◽  
Fang-Fang Peng ◽  
Jia-Lin Li ◽  
Feng Ye ◽  
Shao-Qing Lei ◽  
...  
Keyword(s):  
Renal Disease ◽  
High Glucose ◽  
Mesangial Cells ◽  
Src Kinase ◽  
Specific Inhibitor ◽  
Membrane Translocation ◽  
Caveolin 1 ◽  
Rhoa Activation ◽  
Diabetic Renal Disease ◽  
Src Activation

Glomerular matrix accumulation is a hallmark of diabetic renal disease. Serine/threonine kinase PKC-β1 mediates glucose-induced Akt S473 phosphorylation, RhoA activation, and transforming growth factor (TGF)-β1 upregulation and finally leads to matrix upregulation in mesangial cells (MCs). It has been reported that glucose-induced PKC-β1 activation is dependent on caveolin-1 and the presence of intact caveolae in MCs; however, whether activated PKC-β1 regulates caveolin-1 expression and phosphorylation are unknown. Here, we showed that, although the caveolin-1 protein level had no significant change, the PKC-β-specific inhibitor LY-333531 blocked caveolin-1 Y14 phosphorylation in high glucose (HG)-treated MCs and in the renal cortex of diabetic rats. The Src-specific inhibitor SU-6656 prevented the HG-induced association between PKC-β1 and caveolin-1 and PKC-β1 membrane translocation, whereas PKC-β1 small interfering RNA failed to block Src activation, indicating that Src kinase is upstream of PKC-β1 activation. Although LY-333531 blocked PKC-β1 membrane translocation, it had no effect on the PKC-β1/caveolin-1 association, suggesting that PKC-β1 activation requires the interaction of caveolin-1 and PKC-β1. PKC-β1-mediated Akt S473 phosphorylation, RhoA activation, and fibronectin upregulation in response to HG were prevented by SU-6656 and nonphosphorylatable mutant caveolin-1 Y14A. In conclusion, Src activation by HG mediates the PKC-β1/caveolin-1 association and PKC-β1 activation, which assists in caveolin-1 Y14 phosphorylation by Src kinase. The downstream effects, including Akt S473 phosphorylation, RhoA activation, and fibronectin upregulation, require caveolin-1 Y14 phosphorylation. Caveolin-1 is thus an important mediator of the profibrogenic process in diabetic renal disease.

scholarly journals Inhibition of Src Kinase Blocks High Glucose-Induced EGFR Transactivation and Collagen Synthesis in Mesangial Cells and Prevents Diabetic Nephropathy in Mice

Diabetes ◽  
2013 ◽  
Vol 62 (11) ◽  
pp. 3874-3886 ◽  
Author(s):  
K. Taniguchi ◽  
L. Xia ◽  
H. J. Goldberg ◽  
K. W. K. Lee ◽  
A. Shah ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Collagen Synthesis ◽  
Mesangial Cells ◽  
Src Kinase ◽  
Egfr Transactivation

High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation

2012 ◽  
Vol 302 (1) ◽  
pp. F159-F172 ◽  
Author(s):  
Y. Zhang ◽  
F. Peng ◽  
B. Gao ◽  
A. J. Ingram ◽  
J. C. Krepinsky
Keyword(s):  
Diabetic Nephropathy ◽  
Nadph Oxidase ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Ros Generation ◽  
Caveolin 1 ◽  
Rhoa Activation ◽  
Rhoa Signaling ◽  
Tgf Β1

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We previously showed that RhoA activation by high glucose in mesangial cells (MC) leads to matrix upregulation (Peng F, Wu D, Gao B, Ingram AJ, Zhang B, Chorneyko K, McKenzie R, Krepinsky JC. Diabetes 57: 1683–1692, 2008). Here, we study the mechanism whereby RhoA is activated. In primary rat MC, RhoA activation required glucose entry and metabolism. Broad PKC inhibitors (PMA, bisindolylmaleimide, Gö6976), as well as specific PKCβ blockade with an inhibitor and small interfering RNA (siRNA), prevented RhoA activation by glucose. PKCβ inhibition also abrogated reactive oxygen species (ROS) generation by glucose. The ROS scavenger N-acetylcysteine (NAC) or NADPH oxidase inhibitors apocynin and DPI prevented glucose-induced RhoA activation. RhoA and some PKC isoforms localize to caveolae. Chemical disruption of these microdomains prevented RhoA and PKCβ1 activation by glucose. In caveolin-1 knockout cells, glucose did not induce RhoA and PKCβ1 activation; these responses were rescued by caveolin-1 reexpression. Furthermore, glucose-induced ROS generation was significantly attenuated by chemical disruption of caveolae and in knockout cells. Downstream of RhoA signaling, activator protein-1 (AP-1) activation was also inhibited by disrupting caveolae, was absent in caveolin-1 knockout MC and rescued by caveolin-1 reexpression. Finally, transforming growth factor (TGF)-β1 upregulation, mediated by AP-1, was prevented by RhoA signaling inhibition and by disruption or absence of caveolae. In conclusion, RhoA activation by glucose is dependent on PKCβ1-induced ROS generation, most likely through NADPH oxidase. The activation of PKCβ1 and its downstream effects, including upregulation of TGF-β1, requires caveolae. These microdomains are thus important mediators of the profibrogenic process associated with diabetic nephropathy.

Trigonelline induces autophagy to protect mesangial cells in response to high glucose via activating the miR-5189-5p-AMPK pathway

Phytomedicine ◽  
2021 ◽  
pp. 153614
Author(s):  
Chen Chen ◽  
Jiulong Ma ◽  
Chun Sheng Miao ◽  
Huayu Zhang ◽  
Ming Zhang ◽  
...  
Keyword(s):  
High Glucose ◽  
Mesangial Cells ◽  
Ampk Pathway

scholarly journals Circ-ACTR2 aggravates the high glucose-induced cell dysfunction of human renal mesangial cells through mediating the miR-205-5p/HMGA2 axis in diabetic nephropathy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jie Yun ◽  
Jinyu Ren ◽  
Yufei Liu ◽  
Lijuan Dai ◽  
Liqun Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Cell Injury ◽  
Mesangial Cells ◽  
Protein Detection ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Dysfunction

Abstract Background Circular RNAs (circRNAs) have been considered as pivotal biomarkers in Diabetic nephropathy (DN). CircRNA ARP2 actin-related protein 2 homolog (circ-ACTR2) could promote the HG-induced cell injury in DN. However, how circ-ACTR2 acts in DN is still unclear. This study aimed to explore the molecular mechanism of circ-ACTR2 in DN progression, intending to provide support for the diagnostic and therapeutic potentials of circ-ACTR2 in DN. Methods RNA expression analysis was conducted by the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Cell growth was measured via Cell Counting Kit-8 and EdU assays. Inflammatory response was assessed by Enzyme-linked immunosorbent assay. The protein detection was performed via western blot. Oxidative stress was evaluated by the commercial kits. The molecular interaction was affirmed through dual-luciferase reporter and RNA immunoprecipitation assays. Results Circ-ACTR2 level was upregulated in DN samples and high glucose (HG)-treated human renal mesangial cells (HRMCs). Silencing the circ-ACTR2 expression partly abolished the HG-induced cell proliferation, inflammation and extracellular matrix accumulation and oxidative stress in HRMCs. Circ-ACTR2 was confirmed as a sponge for miR-205-5p. Circ-ACTR2 regulated the effects of HG on HRMCs by targeting miR-205-5p. MiR-205-5p directly targeted high-mobility group AT-hook 2 (HMGA2), and HMGA2 downregulation also protected against cell injury in HG-treated HRMCs. HG-mediated cell dysfunction was repressed by miR-205-5p/HMGA2 axis. Moreover, circ-ACTR2 increased the expression of HMGA2 through the sponge effect on miR-205-5p in HG-treated HRMCs. Conclusion All data have manifested that circ-ACTR2 contributed to the HG-induced DN progression in HRMCs by the mediation of miR-205-5p/HMGA2 axis.

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